Interaction of aging with lipoxygenase deficiency initiates hypersplenism, cardiac dysfunction, and profound leukocyte directed non-resolving inflammation.
Interaction of aging with lipoxygenase deficiency initiates hypersplenism, cardiac dysfunction, and profound leukocyte directed non-resolving inflammation.
复制标题
衰老与脂氧合酶缺乏的相互作用会引发脾功能亢进、心脏功能障碍和严重的白细胞导向的非解决性炎症。
DOI：
10.1007/s11357-021-00496-x
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发表时间：
2022
期刊：
影响因子：
5.6
通讯作者：
Halade,GaneshV
中科院分区：
文献类型：
--
作者：
Kain,Vasundhara;Mat,Yusuf;Halade,GaneshV
在生理性心脏修复过程中，脾白细胞激活的脂氧合酶（LOX）是脾心急性炎症活动过程中一个重要环节，参与特异性促分解脂质介质的生物合成。相比之下，年轻的12/15 LOX −/−小鼠在心肌梗死后使用一种代偿机制，放大环氧二十碳三烯酸介质，改善心脏修复，功能和生存。接下来，我们测试了12/15 LOX的缺失是否影响了渐进性衰老中慢性炎症的发生。为了检验衰老的风险因素，我们使用器官间假说，评估了与年龄相关的12/15 LOX −/−衰老小鼠（2个月、6个月、13个月）的心脏和脾脏白细胞群沿着炎症标志物的数量，并与作为对照（2个月）的C57 BL/6 J（WT;野生型）进行了比较。12/15 LOX −/−衰老小鼠表现出与年龄相关的脾脏质量增加（脾功能亢进）和边缘区面积减少。结果表明，与WT对照组相比，12/15 LOX −/−衰老小鼠的心脏中以炎症介质（PGD 2）水平为标志的间质纤维化增加。从细胞的角度来看，免疫细胞的定量测量表明，与WT对照组相比，12/15 LOX −/−衰老小鼠的心脏和脾脏白细胞（CD 11b+和F4/80+群体）减少。在分子水平上，对心脏和脾脏中细胞因子的分析表明，在脾脏中缺乏12/15 LOX衍生介质的情况下，IFN-γ表达减少，考克斯-1、考克斯-2和ALOX 5表达减少。因此，12/15 LOX −/−小鼠的衰老增加了脾脏质量，改变了脾脏和心脏结构，激活了多种分子和细胞途径，导致与年龄相关的整合和器官间炎症。
In the process of physiological cardiac repair, splenic leukocyte-activated lipoxygenases (LOXs) are essential for the biosynthesis of specialized pro-resolving lipid mediators as a segment of an active process of acute inflammation in splenocardiac manner. In contrast, young 12/15LOX−/−mice use a compensatory mechanism that amplifies epoxyeicosatrienoic acid mediators after myocardial infarction, improving cardiac repair, function, and survival. Next, we tested whether deletion of 12/15LOX impacted the genesis of chronic inflammation in progressive aging. To test the risk factor of aging, we used the inter-organ hypothesis and assessed heart and spleen leukocyte population along with the number of inflammation markers in age-related 12/15LOX−/−aging mice (2 months, 6 months, 13 months) and compared with C57BL/6 J (WT; wild type) as controls (2 months). The 12/15LOX−/−aging mice showed an age-related increase in spleen mass (hypersplenism) and decreased marginal zone area. Results suggest increased interstitial fibrosis in the heart marked with the inflammatory mediator (PGD2) level in 12/15LOX−/−aging mice than WT controls. From a cellular perspective, the quantitative measurement of immune cells indicates that heart and spleen leukocytes (CD11b+and F4/80+population) were reduced in 12/15LOX−/−aging mice than WT controls. At the molecular level, analyses of cytokines in the heart and spleen suggest amplifiedIFN-γ, with reducedCOX-1,COX-2, andALOX5expression in the absence of 12/15LOX-derived mediators in the spleen. Thus, aging of 12/15LOX−/−mice increased spleen mass and altered spleen and heart structure with activation of multiple molecular and cellular pathways contributing to age-related integrative and inter-organ inflammation.